Modulation of mucosal and systemic immunity by hormonal contraceptive use ABSTRACT Growing feminization of the HIV pandemic has created an even greater need for research that will improve our understanding of risk factors promoting transmission of HIV to women. Many epidemiological investigations indicate there may be connections between hormonal contraceptive use and enhanced susceptibility for HIV acquisition, but substantial study limitations hypothesis of our proposal is that progestin-based hormonal contraceptives inhibit genital tract immune responses and tip the balance of protective immunity at genital mucosal surfaces towards acquisition of infection. This hypothesis is based on novel demonstration in our murine model of viral mucosal infection that dendritic cell (DC) activation, virus-specific T cell expansion, and memory T cell development are suppressed among mice administered depot-medroxyprogesterone acetate (DMPA) prior to infection. Notably, our preliminary studies were able to demonstrate that antigen presenting cells (APCs) activated directly ex vivo from women using DMPA also have a decreased ability to induce allogeneic T cell proliferation. These results helped generate a fresh approach to this research question that focuses on the immunomodulatory effects of DMPA, oral contraceptives (OC), and levonorgestrel-containng intrauterine devices (LNG-IUD) that may impair host responses against viral pathogens. Incorporating methods similar to ones developed in our preliminary investigations, we will utilize APCs isolated from the blood and cervixes of women before (enrollment) and after (1 month follow-up visit) they initiate use of OC, DMPA, or LNG-IUD in order to determine the effects of these drugs on APC ability to up-regulate co-stimulatory molecule expression and induce ex vivo T cell proliferation (Aim 1). Cervical secretions collected from women at both study visits will be used to compare concentrations of several innate immune response elements, while cervical tissue will also be used to compare inflammatory and antiviral cytokine production by cervical cells stimulated ex vivo with a Toll-lik receptor 3 agonist (Aim 2). In Aim 2, we will also determine if OC, DMPA, or LNG-IUD use elicits any decreases in cervical epithelial layer thickness or any increases in the exposure of Langerhans cells to the mucosal surface. Completion of these research aims would provide the first comparative evaluation of the capacity of OCP, DMPA, and LNG-IUD to suppress host responses needed to combat genital tract infection, and would also supply healthcare providers more informed recommendations regarding the most appropriate choices for hormonal contraception among women at risk for HIV. PUBLIC HEALTH RELEVANCE: Increasing feminization of the HIV epidemic demands more complete delineation of the relationships between hormonal contraceptive use and susceptibility to HIV infection. This project investigates changes to systemic and genital tract immune responses elicited by oral, injectable, and intrauterine hormonal contraceptives that may impair a woman's ability to combat viral infection. Completion of this proposal will determine biological plausibility of suspected associations between hormonal contraceptive and increased susceptibility to HIV, and supply healthcare providers more informed recommendations regarding apt hormonal contraceptive choices among women at risk for HIV infection.